JP6360113B2 - ホウ素含有化合物 - Google Patents
ホウ素含有化合物 Download PDFInfo
- Publication number
- JP6360113B2 JP6360113B2 JP2016148978A JP2016148978A JP6360113B2 JP 6360113 B2 JP6360113 B2 JP 6360113B2 JP 2016148978 A JP2016148978 A JP 2016148978A JP 2016148978 A JP2016148978 A JP 2016148978A JP 6360113 B2 JP6360113 B2 JP 6360113B2
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- JP
- Japan
- Prior art keywords
- salt
- alkyl
- group
- boron
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims description 97
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims description 70
- 229910052796 boron Inorganic materials 0.000 title claims description 69
- 150000003839 salts Chemical class 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 229910052717 sulfur Inorganic materials 0.000 claims description 55
- -1 hydroxy C 6 Chemical compound 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 33
- 206010028980 Neoplasm Diseases 0.000 claims description 29
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 29
- 150000001768 cations Chemical class 0.000 claims description 23
- 150000001413 amino acids Chemical class 0.000 claims description 22
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 150000002772 monosaccharides Chemical class 0.000 claims description 11
- FULZLIGZKMKICU-UHFFFAOYSA-N N-phenylthiourea Chemical class NC(=S)NC1=CC=CC=C1 FULZLIGZKMKICU-UHFFFAOYSA-N 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 claims description 10
- 229960004705 kojic acid Drugs 0.000 claims description 10
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 150000007523 nucleic acids Chemical class 0.000 claims description 8
- 102000039446 nucleic acids Human genes 0.000 claims description 8
- 108020004707 nucleic acids Proteins 0.000 claims description 8
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 8
- 101000845237 Cereibacter sphaeroides Tryptophan-rich sensory protein Proteins 0.000 claims description 7
- 101000845206 Homo sapiens Putative peripheral benzodiazepine receptor-related protein Proteins 0.000 claims description 7
- 101000845233 Homo sapiens Translocator protein Proteins 0.000 claims description 7
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims description 7
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 7
- 102100031274 Translocator protein Human genes 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 7
- 235000021283 resveratrol Nutrition 0.000 claims description 7
- 229940016667 resveratrol Drugs 0.000 claims description 7
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 claims description 6
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 claims description 6
- 229960002749 aminolevulinic acid Drugs 0.000 claims description 6
- 235000004883 caffeic acid Nutrition 0.000 claims description 6
- 229940074360 caffeic acid Drugs 0.000 claims description 6
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 102000009206 Translocator proteins Human genes 0.000 claims description 5
- 108050000091 Translocator proteins Proteins 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 159000000000 sodium salts Chemical group 0.000 claims description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 3
- FVFNAQKJUNHKAF-UHFFFAOYSA-N CC(C(=O)N)(C1=NNC=2C=NC=NC21)C Chemical compound CC(C(=O)N)(C1=NNC=2C=NC=NC21)C FVFNAQKJUNHKAF-UHFFFAOYSA-N 0.000 claims description 3
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical class C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims description 2
- 125000000981 3-amino-3-oxopropyl group Chemical group [H]C([*])([H])C([H])([H])C(=O)N([H])[H] 0.000 claims description 2
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000006301 indolyl methyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 150000001639 boron compounds Chemical class 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- NFIVJOSXJDORSP-QMMMGPOBSA-N (2s)-2-amino-3-(4-boronophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1 NFIVJOSXJDORSP-QMMMGPOBSA-N 0.000 description 10
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- 238000004519 manufacturing process Methods 0.000 description 10
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- 238000002360 preparation method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
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- 208000032612 Glial tumor Diseases 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
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Description
-R1は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わし;
-R2は、−(CH2)m−X2−R4(mは0〜8の整数を表わし;X2は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R4は、アミノ酸類、アミノ酸アミド、5−アミノレブリン酸、コウジ酸またはその塩、ハイドロキノンまたはその塩、レスベラトロールまたはその塩、DPA(ジメチルピラゾロピリミジンアセトアミド)型TSPO(トランスロケータープロテイン)リガンド、カフェ酸またはその塩、単糖類またはその塩、および核酸またはその構成成分またはそれらの塩からなる群より選択される腫瘍認識部位を表わす)、または不存在であり;
M+は、アルカリ金属イオン、アンモニウムイオンあるいはテトラアルキルアンモニウムイオン(NR4+)、またはテトラフェニルホスホニウムイオンを表わす。
(-R11は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わす)
で表される化合物;と、
R12−(CH2)m−X2−R4(mは0〜8の整数を表わし;X2は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R4は、アミノ酸類、アミノ酸アミド、5−アミノレブリン酸、コウジ酸またはその塩、ハイドロキノンまたはその塩、レスベラトロールまたはその塩、DPA(ジメチルピラゾロピリミジンアセトアミド)型TSPO(トランスロケータープロテイン)リガンド、カフェ酸またはその塩、単糖類またはその塩、および核酸またはその構成成分またはそれらの塩からなる群より選択される腫瘍認識部位を表わし、R12はハロゲンを表わす)とを反応させる工程を含む、下記式のホウ素含有化合物
R11−R13
(ここでR11は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わし;R13は、ハロゲンを表わす)
で表される化合物とを反応させる工程を含むホウ素含有化合物
-R1は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わす。ここで、R1の、−(CH2)n−X1−R3は、その左端部が、式(I)におけるS原子側を示す。
デシル、イコシル、イソオクチル、C6〜C16シクロアルキルなどが例示される。特に好ましくは直鎖状のC8〜C16アルキルである。
一般式(2a):
R11−R13 (2a)
(式中、R11は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わし;
R13は、ハロゲンである)で表される化合物
と反応させることで、本発明のホウ素含有化合物を製造することができる。
(R11は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わす)
で表される化合物;と、
R12−(CH2)m−X2−R4(mは0〜8の整数を表わし;X2は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R4は、アミノ酸類、コウジ酸またはその塩、ハイドロキノンまたはその塩、レスベラトロールまたはその塩、ベンゾジアゼピン型TSPO(トランスロケータープロテイン)リガンド、単糖類またはその塩、または核酸からなる群より選択される腫瘍認識部位を表わし;R12は、ハロゲンを表わす)とを反応させる工程を含む。
・NMRスペクトル:日本電子 JMTC−400/54/SS 400 MHz(日本電子社製)。特に明記しない限り、内部標準としてTMSを用いた。また、下記ケミカルシフトはδ値で示した。
・カラムクロマトグラフィー用シリカゲル:BW−200(富士シリシア社製)。
・融点:BUCHI Melting point B-545を用いて測定した。
・IR:JASCO FT/IR-460 plusを用いて測定した。
S-n-オクチル-チオウンデカヒドロ-クロソ-ドデカボレート2ナトリウム塩の製造
S-(2-シアノエチル)-チオウンデカヒドロ-クロソ-ドデカボレート2テトラメチルアンモニウム塩(250mg, 0.685mmol)をアセトニトリル(10mL)に溶解させ、1-ブロモオクタン(142μL, 0.822mmol)を加え、24時間加熱還流した。反応混合物を濃縮乾固した後に、アセトン(100mL)を加え、不溶物をろ去した。ろ液に25%テトラメチルアンモニウムヒドロキシド/メタノール(250mg, 0.685mmol)を加え、生じた沈殿物をろ取し、アセトンで洗浄した。得られた無色固体をH2O(100mL)に溶かし、amberlite IR120(H+)(5.0mL)を加え、30分静置した。反応混合物をろ過し、ろ液を1N NaOHで中和後、濃縮乾固し、無色不定形固体として目的化合物(159mg, 72.0%)を得た。
1H NMR(DMSO-d6): 0.25-1.65(m, 26H), 2.08-2.09 (m, 2H), 2.19-2.23 (m, 2H)
(S-((3-アミノ-3-ヒドロキシカルボニルブチル)オクチル)-λ3-スルファネイル) ウンデカヒドロ-クロソ-ドデカボレート ナトリウム塩の製造
実施例1で得られたS-n-オクチル-チオウンデカヒドロ-クロソ-ドデカボレート2ナトリウム塩(122 mg, 0.338 mmol)をアセトニトリル (10mL)に溶解させ、(S)-(+)-2-アミノ-4-ブロモブタン酸臭素酸塩(119 mg, 0.453mmol)を加え、24時間加熱還流を行った。反応混合物を濃縮乾固した後に、アセトン(100mL)を加え、不溶物をろ去した。ろ液を濃縮した後にODSカラムクロマトグラフィー(H2O-80%H2O/MeCN)で精製後、凍結乾燥することによって、無色粉体として目的化合物(110mg, 81.3%)を得た。
1H NMR(D2O): 0.55-1.65(m, 24H), 2.20-2.50 (m, 1H), 3.85-3.29 (m, 4H), 3.79-3.87 (m, 1H).
(S-((5-ヒドロキシ-4-オキソ-4H-ピラン-2-イル)メチル)オクチル)-λ3-スルファネイル) ウンデカヒドロ-クロソ-ドデカボレート ナトリウム塩の製造
実施例1で得られたS-n-オクチル-チオウンデカヒドロ-クロソ-ドデカボレート2ナトリウム塩(173 mg, 0.535 mmol)をアセトニトリル (10mL)に溶解させ、2-ブロモメチル-5-ヒドロキシ-4H-ピラン-オン (131 mg, 0.639 mmol)を加え、24時間加熱還流を行った。反応混合物を濃縮乾固した後に、アセトン(100mL)を加え、不溶物をろ去した。ろ液を濃縮した後にODSカラムクロマトグラフィー(H2O-70%H2O/MeCN)で精製後、凍結乾燥することによって、無色粉体として目的化合物(184 mg, 80.8%)を得た。
1H NMR(DMSO-d6): 0.60-1.85(m, 26H), 3.05-3.09 (m, 2H), 4.12-4.31 (m, 2H), 6.61 (s, 1H), 7.09 (s, 1H).
実施例で得たホウ素含有化合物(ホウ素薬剤)について、下記のように生物学的アッセイを行い、細胞毒性、がん細胞への取込みおよび中性子照射による殺細胞効果について、評価する。
96ウェルのマイクロプレートを用い、1ウェルあたりに1.5X104cell/mlの濃度のラットグリーマ細胞(C6)またはメラノーマ細胞(B16)を播取し、室温(37℃、5%CO2)で24時間培養を行なった。培養液を吸引除去し、実施例で得たホウ素含有化合物を種々の濃度で含む培養液を100μLずつそれぞれのウェルに加えた。室温(37℃、5%CO2)で24時間培養後、培養液を吸引除去し、100μLのWST−8溶液をそれぞれ加え、さらに4時間室温(37℃、5%CO2)で培養を行なった。マイクロプレートリーダーを用いて450nm(リファレンス波長:655nm)の波長を測定し、細胞を含まないウェルの吸光度をバックグランドコントロールとした。これにより各IC50値を決定した。
腫瘍細胞へのホウ素含有化合物の取り込み試験
1.5X107cellのラットグリオーマ細胞(C6)またはメラノーマ細胞(B16)を播取し、24時間室温(37℃、5%CO2)で培養を行なった。培養液を吸引除去し、各ホウ素薬剤を0.2mM含む培養液を加え、さらに24時間室温(37℃、5%CO2)で培養を行なった。培養液を吸引除去後、PBSを用いて細胞を3回洗浄した後に、トリプシン処理を行い、細胞を回収した。回収した細胞数をカウントし、HClO4(60%、0.3ml)とH2O2(31%、0.6ml)を1時間、75℃に加熱して灰化溶液を作成した。メンブランフィルターを用いて灰化溶液をろ過し、ICP−AESを用いて溶液中のホウ素濃度を測定することによって、細胞内のホウ素濃度を決定した。
中性子照射による腫瘍細胞に対する殺細胞効果
5.0X106cellの細胞を播取し、24時間室温(37℃、5%CO2)で培養を行なう。培養液を吸引除去し、各ホウ素薬剤を2.0mM含む培養液を加え、さらに6時間室温(37℃、5%CO2)で培養を行なう。培養液を吸引除去後、PBSを用いて細胞を3回洗浄した後に、トリプシン処理を行い、細胞を回収する。回収した細胞を培養液に懸濁させ、5.0X103cell/mlの濃度に調製し、この懸濁液1mlをテフロンチューブに移す。細胞溶液を入れたテフロンチューブに対して、熱中性子線を0〜4.3×1012cm−2照射し、その細胞を300cellずつ培養液6ml中に播取する。9日間室温(37℃、5%CO2)で培養を行なった後、エタノールを用いてコロニーを固定し、0.1%クリスタルバイオレットで染色してからコロニー数を数えて、殺細胞効果を比較する。
Claims (15)
- 下記式で表わされるホウ素含有化合物の薬学的に許容される塩:
-R1は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わし;
-R2は、−(CH2)m−X2−R4(mは0〜8の整数を表わし;X2は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;
R4は、アミノ酸類、アミノ酸アミド、5−アミノレブリン酸、コウジ酸またはその塩、ハイドロキノンまたはその塩、レスベラトロールまたはその塩、DPA(ジメチルピラゾロピリミジンアセトアミド)型TSPO(トランスロケータープロテイン)リガンド、カフェ酸またはその塩、単糖類またはその塩、および核酸またはその構成成分またはそれらの塩からなる群より選択される腫瘍認識部位を表わす)を表し;および
Mは、単原子陽イオン、多原子陽イオン、または錯陽イオンを表す。 - 前記-R2が、−(CH2)m−X2−R4(mは0〜8の整数を表わし;X2は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;-R4は、
- 前記薬学的に許容される塩が、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アルミニウム塩、アンモニウム塩、テトラアルキルアンモニウム塩、テトラフェニルホスホニウム塩、トリメチルアミン塩、トリエチルアミン塩、ピリジン塩、ピコリン塩、エタールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ジシクロヘキシルアミン塩、又はN,N'−ジベンジルエチレンジアミン塩である、請求項1〜9記載のホウ素含有化合物の薬学的に許容される塩。
- 下記式
(-R11は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、ヒドロキシカルボニルC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキル、または、置換または無置換のベンジル基を表わす)、または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わす)で表わされる化合物の薬学的に許容される塩;と、
R12−(CH2)m−X2−R4(mは0〜8の整数を表わし;X2は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R4は、アミノ酸類、アミノ酸アミド、5−アミノレブリン酸、コウジ酸またはその塩、ハイドロキノンまたはその塩、レスベラトロールまたはその塩、DPA(ジメチルピラゾロピリミジンアセトアミド)型TSPO(トランスロケータープロテイン)リガンド、カフェ酸またはその塩、単糖類またはその塩、および核酸またはその構成成分またはそれらの塩からなる群より選択される腫瘍認識部位を表わし、R12はハロゲンを表わし、Mは、単原子陽イオン、多原子陽イオン、または錯陽イオンを表す)とを反応させる工程を含む、下記式のホウ素含有化合物の薬学的に許容される塩
の合成方法。 - 下記式のホウ素含有化合物の薬学的に許容される塩
R11−R13
(ここでR11は、−(CH2)n−X1−R3(nは、0〜6の整数を表わし;X1は、O、S、NH、S−S、O−CO、NHCO、またはSCOを表わすか、不存在であり;R3は、C6〜C20アルキル、ヒドロキシC6〜C20アルキル、アミノC6〜C20アルキル、アジドC6〜C20アルキル、置換または無置換のフェノキシC6〜C20アルキル、置換または無置換のフェニルチオウレアC6〜C20アルキルを表わす)、
または、−(CH2)2−O−の繰り返し配列を3回以上10回以下有しかつ酸素原子側の末端にメチル基またはエチル基を有する基を表わし;R13は、ハロゲンを表わす)で表される化合物とを反応させる工程を含むホウ素含有化合物の薬学的に許容される塩
の合成方法。 - 請求項1から請求項10までのいずれかに記載のホウ素化合物の薬学的に許容される塩を1種または2種以上含有する医薬組成物。
- BNCTによるガン治療用である、請求項14に記載の医薬組成物。
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